The major thrust of this study is to identify new germline polymorphisms in micro-RNAs (miRs) that are associated with increased risk of developing lung cancer (LC) or provide LC prognostic information. Such loci will be important in early cancer detection and patient management. In addition, we want to determine if miRs provide a blood biomarker for LC detection and if certain miR biomarkers also play a functional role in LC pathogenesis. miRNAs are a class of small non-coding endogenous RNAs capable of regulating an estimated third of human genes. miRNAs can function as oncogenes or tumor suppressor genes depending on the cellular context. In cancer, dysregulation of tumor suppressive or oncogenic miRNAs could have profound effects on various cellular processes including proliferation, differentiation, and cell death. miRNA relevant genomic variations may have regulatory effects on gene expression and cellular processing by altering gene splicing, modulating miRNA-target interaction, and disrupting miRNA biogenesis. However, no studies have systematically screened and validated SNPs in miRNA pathways as modulators of LC risk and outcomes. One of the added advantages of miRNA and miR pathway targeted study of SNPs (miR-SNPs) is that most miR-SNPs are not covered by current GWAS chips. Therefore, we propose to conduct a systematic analysis of SNPs in miRs and miR pathway(s) as susceptibility factors for NSCLC risk and clinical outcome, incorporating germline miR-SNP genotyping, somatic miRNA profiling, circulating miRNA detection, and functional characterization. This proposal builds upon a rich specimen repository, well annotated with comprehensive epidemiologic, clinical and genetic data, from one of the largest LC studies in the U. S., MD Anderson LC Study, along with the Harvard LC study. The four specific aims are: Aim 1) To screen and validate a custom array of ~6,000 miR-SNPs as predictors of NSCLC risk using a three-stage design (discovery, internal and external validation) in a total of 4,800 Caucasian cases and 4,800 matched controls, as well as 1,600 pairs of African American cases and controls; Aim 2) To screen and validate the above 6,000 miR-SNPs as predictors of NSCLC recurrence in the subset of surgically resected early stage NSCLC patients using a similar three-stage design; Aim 3) To identify circulating miRNAs as predictors for recurrence in early stage NSCLC using a testing and validation design; Aim 4) To determine the functional impact on lung cancer of significant miR-SNPs and miRNAs identified from the above aims.